1-alkylsulfonyl-4-alkyl piperazines



Patented May 9, 1950 UNITED STATES @TENT OFFICE I-ALKYLSULFONYL-I-ALKYL PIPERAZINES Robert Michel Jacob, Ablon-sur-Seine, France, assignor to Societe des Usines Chimiques Rhone- Poulenc, Paris, France, a corporation of France No Drawing. Application January 4, 1949, Serial No. 69,241. In France March 5, 1948 5 Claims.

1 The present invention has for its object to provide new therapeutically interesting derivatives of piperazine of the general formula:

v wherein R represents a member of the class consisting of alkyl radicals containing from 1 to 4 carbon atoms and phenyl radicals which may be substituted by a member of the class consisting of lower alkyls, amino, methoxy and ethoxy groups, and halogen atoms, and R1 represents an alkyl radical containing not more than 3 carbon atoms. By the expression lower alkyl is meant a group selected from the class consisting of methyl, ethyl and propyl groups.

According to a feature of the present invention these new compounds are to be obtained by the following methods:

(2') Condensation of a sulphonyl halide of the type R-SO2X (where X represents a halogen atom), with an N-mono-substituted piperazine.

(ii) Cyclisation of a halogenated derivative CH-,'CH2-X RSOR-N OH2CH2X (X being a halogen atom), by condensation with a secondary amine NH(R1)2 and conversion of the quaternary derivative obtained into the corresponding substituted piperazine by known methods.

(iii) Cyclisation of a halogenated derivative (X being a halogen atom) by condensation with a primary amine R1--NH2.

The derivatives OH2-CH2X R-soi-N CHa-CHr-X can be prepared either by condensation of sulphonyl halides of the type R--SO:X with the secondary halogenated amines:

om-om-X \C Ha-CHrX or from the corresponding hydroxy compounds:

0H, cm011 R-SOaN GH2CH2OH by replacing the hydroxyl groups by halogen in manner known per se (for example by the action of thionyl chloride). The hydroxy-substituted sulphonamides can themselves be obtained by the action of the sulphonyl halides R-SOz-X on di-ethanolamine:

(iv) Action of an alkylating agent, such as a methyl or ethyl halide or the corresponding sulphonate on the sulphonylpiperazinez The products of the invention possess interesting physiological properties; in particular. they have been found very effective in treating conditions of traumatic and haemorrhagic shock. 1-ethanesulphonyl-4-ethyl piperazine constitutes one of the preferred products of the invention by reason of its outstanding activity in this respect.

The following non-limitative examples show how the invention can be carried into effect. The melting points referred to (unless otherwise stated) were determined by the capillary method.

Example 1 way, 13 g. of 1-ethanesulphonyl-4-ethyl piperazine boiling at 126l27 C. under 0.7 mm. of mercury are obtained. The hydrochloride of this product melts at 178-178.5 C. The ethlodide melts at 202 C. (instantaneous melting point on the Maquenne block).

Example 2 Following the method of Example 1, but employing 8 g. ofmethanesulphonyl chloride, 10 g. of l-methanesulphonyl-4-ethyl piperazine having a melting point of 80 C. are obtained after recrystallisation from ether.

Example 3 To a well agitated, cooled solution of 20 g. of N-methyl-piperazine in 100 cc. of ether, a solution of 12.85 g. of ethanesulphonyl chloride in 100 cc. of ether is gradually added in such a manner that the temperature does not exceed 15 C. After being allowed to stand for one hour at room temperature the mixtureis taken upinan-excess of dilute sulphuric .acid. The mixture. is then centrifuged and the solution obtained allowed to stand whereupon the aqueous acid layer which separates is decanted, rendered .alkaline with caustic soda and salted with a saturated solution of potassium carbonate. {Ihebase which .separates out is extracted with-ether and thee'thereal solutions are dried over sodium sulphate. 'Upon evaporation of the ether, l6.g..of .l-ethanesul phony-l-methyl piperazine are obtained which, when distilled (boiling point under 0.9 mm. of mercury=l20 0.), solidifies in the form of-white crystals having a melting point of 34-35 C.

Example 4 Following .the procedure-of. Example .1, but meplacing the N-ethyl piperazineby 125g. of .N-

isopropylpiperazine with 6.3 g. of ethanesulphonyl chloride, 7.6 g. of 1-ethanesulphonyl-4-isopropyl piperazine boiling at 129-130 C. under 0.7 mm. of mercury are obtained, .thehydrochloride of this product melting at 212-213 C. (instantaneous 'meltina point on the; Maquenne block).

Example: -5

By following theprocedure of Example 1, but replacing the ethanesulphonyl'.chloride by 13.1 g. of n-propanesulphonyl bromide, 13.3 g. of l-propanesulphonyl-4-ethyl piperazine are obtained in theiorm-of a colourless liquid boiling xatlO-IMZ" C. under 0.9 :mm. of mercury,:the hydrochloride Of which product melts at 18225-188" 0.

Example .6

By following the procedure. of "Example .1, but replacingthe N-ethylpiperazine by 13.8 g. of :N-

.isopropyl piperazine and-replacing the ethanesulphonyl chloride by. 10. 1 g. of isopropanesulphonyl .bromide, there.areobtainedlo g. ofv L-isopropanesulphonyle'i isopropyl piperazine, which boils :at 130 C. under 0.6 mm. of mercury and melts at 485 C. The hydrochloride melts at about 245-250" C. (instantaneous melting pointnnthe :Maquenne block).

Example 7 By following the procedure of Example 1, .but replacing the .ethanesulphonyl chloride by l4 g. of n-butanesulphonyl bromide, there. are obtained 12.8 g. of .1en butanesulphonylerethyl pi razine in the form of a colourless oil which boils .at

131.5-132" C. under 0.45 mm. of mercury .a-ndthe hydrochloride of which meltsat 185-186" '0.

Example 8 .A mixture of 1.4 gof N:N-.di(o-chloroethyl) .benzenesulphonamide having a melting point of 47-48" C. v(olzvtained by the actionof-benzenesulgphonyl chlorideon thehydrochloride of.N:.N-di(o chloroethyD-amine in acetone .in :the .presence of sodium carbonate), 6.75 g. of dimethylamine and cc. of absolute alcohol, is heated in a sealed tube .for 3 .hoursat 130 .C. The .alcohol is evaporated to leave .a solid residue which .is

taken upin alittle .water. The product is then filtered toproduce 13.8 ggofra. moist. crudeproduct which is purified by recrystallisation,fromalcohol and which is l-benzenesulphonyl--methyl piperazine having a meltingzpointof 129-130 C.

Example 9 Amixture ofjZO glof. N benzenesulphonyl piperazine having a .meltingpointof mil-109 C.-(obtamed by hydrolysis .of l-henzenesulphonyl-- carbethoxy piperazine having a melting point of -116 C., which is itselipreparedrby the action .of .benzenesulphonyl chloride. on the known N- carbethoxypiperazine), 20g. of methyl benzene .asulphonate, 7 g. of anhydrous sodium carbonate and 100 cc. of absolute alcohol is heated under reflux until'evolution of carbon dioxide has ceased.

The @mixtureis filtered hot and the alcohol is evaporateditoleare a solid residue which is puri- .;fied by'dissolution in a dilute acid, precipitation .sodasolution (36 B.) after'filter'ing and washing withwater, "10.8 g. of '1-benzenesulphony'l-'4- methyl piperazine identical to "the product described in Example 8 are obtained.

Example 11 A mixture of 20 g.-of N bis tfl-chloroethyllbenzene sulphonamide, IO-g otarihydrousmonoethyl-amine and 2400.- of absoluteal'cohol isheated in a sealed tube for'? hours at -135"C. "When 1 the reaction is complete, the alcohol is evaporated on the water "bath and the 1 residue is taken up in 15 cc. of ice water and filtered. The product is recrystallised'from aqueous-(66%) alcohol. In

this way, 15.3 -g. of 1-benzenesulphonyl 4-ethyl .piperazine having a melting point of 127 C. are

obtained.

Example 12 If, in the process of Example: 11, the ethylamine is replaced bypropylamine (20 g.) there are obtained 15.4 g. of l-benzenesulphonyl-4 propy1 Example 13 'By'following the-procedure pf'Example 1'1, but with 20 g. of isopropylamine instead of "10 guo'f monoethylamine, 19g. of 1-benzenesulphonyl-4- isopropyl piperazineare obtained. Melting point 123-123.3 C.

Erample 14 By .following the procedure of .Example 11; but starting with 4 g. of-N-bisdpechloroethyl) -pchlorobenzene sulphonamide (insteadofN-bis-lfichloroethyl) benzene sulphonamide) and with monoethylamine in aqueous solution (8 00.; concentration 52%) instead of anhydrous monoethylamine, l (p chlorobenzenesulphonyl) -4- ethyl piperazine melting at 78-79 C. is obtained.

Example .15

By following the procedure of Example =14, but with 296 g. of N-bis-(B-chloroethyl)-p-toluenesulphonamide and 350 cc. of an aqueous solution of 9.5 N monomethylamine, there are obtained 209 g. of l-p-toluenesulphonybi-methyl piperazine,xwhichimelts.;at"152453" C.

Example 16 A mixture of 20 g. of NzN-di-(o-chloroethybp-toluenesulphonamide (obtained as described in French ;patent specification No. 906,094), 14 g. of anhydrous diethylamine and..25. cc. .of-absolute alcohol is heated in a sealed tube at 125 C. for 5 hours. The alcohol and the excess diethylamine are distilled under reduced pressure. The residue is taken up in a little water, and an equal volume of a saturated potassium carbonate solution is added. An oily layer separates, is decanted and then distilled under reduced pressure. Water first distils, whereafter a lively reaction takes place at about 250 C. (temperature of the heating bath). 14 g. of an oil (boiling point under 1.2 mm. of mercury=196-198 C.) are recovered and this oil crystallises. By recrystallisation from dilute alcohol, pure l-p-toluenesulphonyl-i-ethyl piperazine is obtained in the form of white crystals having a melting point of 73 C.

Example 17 CHs-CH:

...R Uni-0Q! wherein R represents an alkyl radical containing from 1 to 4 carbon atoms and R1 represents an alkyl radical containing not more than 3 carbon atoms, and their salts.

2. A compound selected from the class consisting of 1-ethanesulphonyl-4-ethyl piperazine and its acid salts.

3. A compound selected from the class consisting of 1-ethanesulphonyl-4-methyl piperazine and its acid salts.

' 4. A compound selected from the class consisting of 1-propanesu1phonyl-4-ethyl piperazine and its acid salts.

5. A process for the production of new therapeutically useful piperazine derivatives which comprises condensing a sulphonyl halide of the type R-SOz-X with an N-R1piperazine, R representing an alkyl radical containing from 1 to 4 carbon atoms and R1 representing an alkyl radical containing not more than 3 carbon atoms and X representing a halogen atom.

ROBERT MICHEL JACOB.

OTHER REFERENCES Kohlbach, Chemical Abstracts, 33, 2897 (1939), citing Archiv. Hem. Farm, 11, 94-123 (1937). Kermack et al., J. Chem. Soc., 1940, 202-205. 

1. NEW THERAPEUTICALLY USEFUL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF DERIVATIVES OF PIPERAZINE OF THE GENERAL FORMULA:
 5. A PROCESS FOR THE PRODUCTION OF NEW THERAPEUTICALLY USEFUL PIPERAZINE DERIVATIVES WHICH COMPRISES CONDENSING A SULPHONYL HALIDE OF THE TYPE R-SO2-X WITH AN N-R1-PIPERIZINE, R REPRESENTING AN ALKYL RADICAL CONTAINING FROM 1 TO 4 CARBON ATOMS AND R1 REPRESENTING AN ALKYL RADICAL CONTAINING NOT MORE THAN 3 CARBON ATOMS AND X REPRESENTING A HALOGEN ATOM. 